The present invention is generally directed to N-alkylpiperazino derivatives of substituted acetic acids and pharmaceutical compositions thereof, to the preparation of such compounds and compositions, and to the use of such compounds and compositions to enhance sexual performance, as pro-libido agents and/or for the treatment and/or prevention of sexual dysfunction in male and/or female animals.
At the present time there is a wide variety of pharmacological agents used and/or reportedly useful as pro-libido agents and/or for the treatment of sexual dysfunction. Some examples include: serotonin receptor agonists and antagonists (see, e.g., EP 385,658; WO 94/15,920; GB 2,248,449; and GB 2,276,165), dopamine receptor agonists (see, e.g., WO 93/23,035; WO 94/21,608; Pomerantz S. M., Pharmacol. Biochem. Behav. 39:123-128, 1991; and Ferrari F. et al. Psychopharmacology 113:172-176, 1993); adrenergic receptor agonists (see, e.g., WO 95/13,072; EP 611,248; U.S. Pat. No. 5,229,387; and WO 92/11,851); inhibitors of phoshodiesterase (see, e.g., DE 4,338,948; and WO 94/28,902); histamine receptor agonists (see, e.g., U.S. Pat. Nos. 4,013,659; 4,126,670; 4,767,778; WO 91/17,146; U.S. Pat. No. 5,047,418; and EP 0,458,661); neuropeptide Y antagonists (see, e.g., WO 95/00,161); angiotensin II receptor antagonists (see, e.g., EP 577,025); cholinesterase inhibitors (see, e.g., U.S. Pat. Nos. 5,177,070; and 4,633,318); combinations of agents with the different types of biological activity (see, e.g., U.S. Pat. No. 5,145,852; and WO 95/05,188); derivatives of vasoactive intestinal peptide (see, e.g., U.S. Pat. No. 5,147,855; EP 540,969; and EP 463,450); prostaglandins (see, e.g., WO 93/00,894; and EP 459,3770); antidepressants and antipsychotics (see, e.g., U.S. Pat. No. 4,931,445; GB 2,448,449; and Naganuma et al. Clin. Exp. Pharm. Physiol. 20:177-183, 1993); nitric oxide donors (see, e.g., WO 92/21,346; DE 4,305,881; DE 4,212,582; and WO 94/16,729); calcitonin gene related peptide (see, e.g., Steif, C. G. et al., Urology, 41:397-400, 1993); and androgens (see, e.g., JP 06,211,675; HU 62,473; and WO 94/16,709).
Many or all of these pharmacological agents are associated with adverse effects, some examples of which are quoted below. Dopamine receptor agonists may aggravate schizophrenia or induce it de novo in some patients. Serotonin receptor agonists are capable of producing an effect that has been termed xe2x80x9cserotonin syndromexe2x80x9d (Glennon, R. A. J. Med. Chem. 30:1-9,1987). This latter effect has been thoroughly investigated in animals (Peroutka, S. J. Science 212:827-829, 1981; Goddwin G. M. et al., Br. J. Pharmacol. 84:743-753, 1985; and Tricklebank, M. D., Eur. J. Pharmac. 117:15-24, 1985) and manifests itself in, for example, head twitches, xe2x80x9cwet dog shakesxe2x80x9d, forepaw treading, flat body posture, hind limb abduction, Straub tail and yawning. Histamine receptor agonists may induce central nervous system dysfunction and adverse effects in the endocrine system. Smooth muscle relaxants (such as papaverine) may induce pain, echytomosis and occasional episodes of priapism. xcex1-Adrenoreceptor blockers administered systemically have been reported to induce priapism characterized by a persistent erection that cannot be relieved by sexual intercourse or masturbation (Kaisary, A. V. et al., Br. J. Urol. 68:227, 1986).
Accordingly there is a need in the art to identify new pharmacological agents, compositions and/or treatments which are useful as pro-libido agents and/or are useful in the treatment and/or prevention of sexual dysfunction in males or females, and/or can enhance a patient""s sexual performance. The present invention fulfills these needs and further provides related advantages.
Briefly, one aspect of the invention provides compounds of formula (I) 
including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof, wherein, independently at each occurrence:
Ar is selected from a C3-C13carbocyclic ring, and ring systems selected from formulae (II), (III), (IV), (V), (VI), and (VII): 
where R7, R8 and R9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, aryl and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C1-C6alkyl; 
where R10 and R11 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C1-C6alkyl; 
where R12 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C1-C6alkyl; 
including isolated enantiomeric, diastereomeric, tautomeric and geometric isomers thereof, and mixtures thereof;
L is selected from the group of a direct bond, O, NH, and N(C1-C6 alkyl);
R1 is selected from the group of a direct bond, a C1-C6 alkylene group, (such as xe2x80x94CH2xe2x80x94 and xe2x80x94CH2CH2xe2x80x94), and 1,2-disubstituted C5-C6 cycloalkyl; and
R2 is C1-C6 alkyl.
Another aspect of the invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent in combination with a compound of formula (I): 
including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof, having the definition set forth above.
Another aspect of the invention provides a method for treating and/or preventing sexual dysfunction in a male or female patient, where the method includes the step of administering to the patient in need thereof an amount of a compound of formula (I) or composition therefrom, 
including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof, having the definition set forth above, and where the amount is effective to treat and/or prevent the sexual dysfunction. The sexual dysfunction may be, for example, male erectile dysfunction or impotence.
Another aspect of the invention provides a use of a compound for manufacture of a medicament for treating and/or preventing sexual dysfunction in a male or female patient, wherein the compound is of formula (I) 
including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof, which has the definition set forth above. The sexual dysfunction may be, for example, male erectile dysfunction or impotence.
Another aspect of the invention provides a method for increasing the libido of a male or female patient, where the method includes the step of administering to a male or female in need thereof an effective amount of a compound, or composition therefrom, of formula (I) 
including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof, which has the definition set forth above, and where the amount is effective to increase the libido of the patient.
Another aspect of the invention provides a use of a compound, or composition therefrom, for manufacture of a medicament for increasing the libido of a male or female patient, wherein the compound is of formula (I) 
including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof, which has the definition set forth above.
Another aspect of the invention provides a method for enhancing the sexual performance of a male or female patient, comprising administering to the patient in need thereof a therapeutically effective amount of a compound, or composition therefrom, of the formula (I) 
including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof, which has the definition set forth above, and wherein the amount increases the sexual performance of the patient.
Another aspect of the invention provides a use of a compound, or composition therefrom, for manufacture of a medicament for enhancing the sexual performance of a male or female patient, wherein the compound is of formula (I) 
including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof, which has the definition set forth above.
Another aspect of the invention is a method for the preparation of a compounds of formula (I) 
including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof, having the definition set forth above. According to the inventive method, a substituted acetic acid compound or activated version thereof having the formula. 
wherein X is OH or an activated (leaving) group such as chloride, is reacted with a compound having the formula 
The reaction provides a bond between Cxe2x95x90O and L as shown in formula 
These and other aspects of the invention will be more fully understood upon reference to the following detailed description and examples.
An understanding of the present invention may be aided by reference to the following definitions and explanation of conventions used herein.
Definitions and Conventions
In the formulae depicted herein, a bond to a substituent and/or a bond that links a molecular fragment to the remainder of a compound may be shown as intersecting one or more bonds in a ring structure. This indicates that the bond may be attached to any one of the atoms that constitutes the ring structure, so long as a hydrogen atom could otherwise be present at that atom. Where no particular substituent(s) is identified for a particular position in a structure, then hydrogen(s) is present at that position.
In those instances where the invention specifies that a non-aromatic ring is substituted with more than one R group, and those R groups are shown connected to the non-aromatic ring with bonds that bisect ring bonds, then the R groups may be present at different atoms of the ring, or on the same atom of the ring, so long as that atom could otherwise be substituted with a hydrogen atom.
Likewise, where the invention specifies compounds containing the Arxe2x80x94CH2C(O)xe2x80x94Lxe2x80x94 group where Ar equals the group (V) 
the invention is intended to encompass compounds wherein xe2x80x94CH2C(O)xe2x80x94Lxe2x80x94 is joined through CH2 to the Ar group (V) at any atom which forms the group (V) so long as that atom of group (V) could otherwise be substituted with a hydrogen atom. Thus, there are seven positions (identified with the letters xe2x80x9caxe2x80x9d through xe2x80x9cgxe2x80x9d) in structure (V) where the xe2x80x94CH2C(O)xe2x80x94Lxe2x80x94 group could be attached, and it is attached at one of those seven positions. The R12 group would occupy one and only one of the remaining six positions, and hydrogen atoms would be present in each of the five remaining positions.
The compounds of the present invention may contain two or more asymmetric carbon atoms and thus exist as enantiomers and diastereomers. Unless otherwise noted, the present invention includes all enantiomeric and diastereomeric forms of the compounds of the invention. Pure stereoisomers, mixtures of enantiomers and/or diastereomers, and mixtures of different compounds of the invention are included within the present invention. Thus, compounds of the present invention may occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. A racemate or racemic mixture does not imply only a 50:50 mixture of stereoisomers. The compounds of formula (I) may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.
The phrase xe2x80x9cindependently at each occurrencexe2x80x9d is intended to mean (i) when any variable occurs more than one time in a compound of the invention, the definition of that variable at each occurrence is independent of its definition at every other occurrence; and (ii) the identity of any one of two different variables (e.g., R1 within the set R1 and R2) is selected without regard the identity of the other member of the set. However, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
In accordance with the present invention and as used herein, the following terms are defined to have following meanings, unless explicitly stated otherwise:
xe2x80x9cAcid addition saltsxe2x80x9d refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid and the like.
xe2x80x9cAcylxe2x80x9d refers to branched or unbranched hydrocarbon fragments terminated by a carbonyl xe2x80x94(Cxe2x95x90O)xe2x80x94 group containing the specified number of carbon atoms. Examples include acetyl [CH3Cxe2x95x90Oxe2x80x94, a C2acyl] and propionyl [CH3CH2Cxe2x95x90Oxe2x80x94, a C3acyl].
xe2x80x9cAlkanoyloxyxe2x80x9d refers to an ester substituent wherein the ether oxygen is the point of attachment to the molecule. Examples include propanoyloxy [(CH3CH2Cxe2x95x90Oxe2x80x94Oxe2x80x94, a C3alkanoyloxy] and ethanoyloxy [CH3Cxe2x95x90Oxe2x80x94Oxe2x80x94, a C2alkanoyloxy].
xe2x80x9cAlkoxyxe2x80x9d refers to an O-atom substituted by an alkyl group, for example, methoxy [xe2x80x94OCH3, a C1alkoxy].
xe2x80x9cAlkoxyalkylxe2x80x9d refers to an alkylene group substituted with an alkoxy group. For example, methoxyethyl [CH3OCH2CH2xe2x80x94] and ethoxymethyl (CH3CH2OCH2xe2x80x94] are both C3alkoxyalkyl groups.
xe2x80x9cAlkoxycarbonylxe2x80x9d refers to an ester substituent wherein the carbonyl carbon is the point of attachment to the molecule. Examples include ethoxycarbonyl [CH3CH2OCxe2x95x90Oxe2x80x94, a C3alkoxycarbonyl] and methoxycarbonyl [CH3OCxe2x95x90Oxe2x80x94, a C2alkoxycarbonyl].
xe2x80x9cAlkylxe2x80x9d refers to a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms and having one point of attachment. Examples include n-propyl (a C3alkyl), iso-propyl (also a C3alkyl), and t-butyl (a C4alkyl).
xe2x80x9cAlkylenexe2x80x9d refers to a divalent radical which is a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms, and having two points of attachment. An example is propylene [xe2x80x94CH2CH2CH2xe2x80x94, a C3alkylene].
xe2x80x9cAlkylcarboxyxe2x80x9d refers to a branched or unbranched hydrocarbon fragment terminated by a carboxylic acid group [xe2x80x94COOH]. Examples include carboxymethyl [HOOCxe2x80x94CH2xe2x80x94, a C2alkylcarboxy] and carboxyethyl [HOOCxe2x80x94CH2CH2xe2x80x94, a C3alkylcarboxy].
xe2x80x9cArylxe2x80x9d refers to aromatic groups which have at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl (also known as heteroaryl groups) and biaryl groups, all of which may be optionally substituted. Carbocyclic aryl groups are generally preferred in the compounds of the present invention, where phenyl and naphthyl groups are preferred carbocyclic aryl groups.
xe2x80x9cAralkylxe2x80x9d refers to an alkylene group wherein one of the points of attachment is to an aryl group. An example of an aralkyl group is the benzyl group [C6H5CH2xe2x80x94, a C7aralkyl group].
xe2x80x9cCycloalkylxe2x80x9d refers to a ring, which may be saturated or unsaturated and monocyclic, bicyclic, or tricyclic formed entirely from carbon atoms. An example of a cycloalkyl group is the cyclopentenyl group (C5H7xe2x80x94), which is a five carbon (C5) unsaturated cycloalkyl group.
xe2x80x9cCarbocyclicxe2x80x9d refers to a ring which may be either an aryl ring or a cycloalkyl ring, both as defined above.
xe2x80x9cCarbocyclic arylxe2x80x9d refers to aromatic groups wherein the atoms which form the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups such as phenyl, and bicyclic carbocyclic aryl groups such as naphthyl, all of which may be optionally substituted.
xe2x80x9cHeteroatomxe2x80x9d refers to a non-carbon atom, where boron, nitrogen, oxygen, sulfur and phosphorus are preferred heteroatoms, with nitrogen, oxygen and sulfur being particularly preferred heteroatoms in the compounds of the present invention.
xe2x80x9cHeteroarylxe2x80x9d refers to aryl groups having from 1 to 9 carbon atoms and the remainder of the atoms are heteroatoms, and includes those heterocyclic systems described in xe2x80x9cHandbook of Chemistry and Physics,xe2x80x9d 49th edition, 1968, R. C. Weast, editor; The Chemical Rubber Co., Cleveland, Ohio. See particularly Section C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems. Suitable heteroaryls include furanyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, and the like.
xe2x80x9cHydroxyalkylxe2x80x9d refers to a branched or unbranched hydrocarbon fragment substituted with an hydroxy (xe2x80x94OH) group. Examples include hydroxymethyl (xe2x80x94CH2OH, a C1hydroxyalkyl) and 1-hydroxyethyl (xe2x80x94CHOHCH3, a C2hydroxyalkyl).
xe2x80x9cThioalkylxe2x80x9d refers to a sulfur atom substituted by an alkyl group, for example thiomethyl (CH3Sxe2x80x94, a C1thioalkyl).
As used herein, the term patient refers to a warm-blooded animal such as a mammal which can and will benefit from the above treatment (curative or prophylactic). It is understood that guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, and humans are examples of male and female patients within the scope of the meaning of the term.
xe2x80x9cPharmaceutically acceptable carriersxe2x80x9d for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remingtons Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). For example, sterile saline and phosphate-buffered saline at physiological pH may be used. Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition. For example, sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid may be added as preservatives. Id. at 1449. In addition, antioxidants and suspending agents may be used. Id.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d refers to salts of the compounds of the present invention derived from the combination of such compounds and an organic or inorganic acid (acid addition salts) or an organic or inorganic base (base addition salts). The compounds of the present invention may be used in either the free base or salt forms, with both forms being considered as being within the scope of the present invention.
The xe2x80x9ctherapeutically effective amountxe2x80x9d of a compound of the present invention will depend on the route of administration, the type of warm-blooded animal being treated, and the physical characteristics of the specific warm-blooded animal under consideration. These factors and their relationship to determining this amount are well known to skilled practitioners in the medical arts. This amount and the method of administration can be tailored to achieve optimal efficacy but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
Compositions described herein as xe2x80x9ccontaining a compound of formula (I)xe2x80x9d encompass compositions that contain more than one compound of formula (I).
Compounds of the Present Invention
As noted above, the present invention is directed toward compounds having formula (I) 
including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof. In the compounds, independently at each occurrence:
Ar is selected from a C3-C13carbocyclic ring, and ring systems selected from formulae (III), (IV), (V), (VI), (VII) and (VIII), wherein compounds having each of the ring systems represented by formulae (II), (III), (IV), (V), (VI), and (VII) independently represent preferred sets of compounds of the invention: 
where R7, R8 and R9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, aryl and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C1xe2x80x94C6alkyl; 
where R10 and R11 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C1-C6alkyl; 
where R12 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C1-C6alkyl; and 
including isolated enantiomeric, diastereomeric, tautomeric, and geometric isomers thereof, and mixtures thereof;
L is selected from the group of a direct bond, O, NH, and N(C1-C6 alkyl);
R1 is selected from a direct bond, a C1-C6 alkylene group (such as xe2x80x94CH2xe2x80x94and xe2x80x94CH2CH2xe2x80x94), and 1,2-disubstituted C5-C6 cycloalkyl; and
R2 is C1-C6 alkyl.
These compounds may be collectively referred to herein as xe2x80x9ccompounds of the inventionxe2x80x9d or xe2x80x9cthe inventive compoundsxe2x80x9d or xe2x80x9csubstituted acetic acid derivatives of the inventionxe2x80x9d, or the like. In a preferred embodiment, Ar is an aryl group.
In general, compounds of the present invention may be in the form of a solvate or salt, preferably a pharmaceutically acceptable solvate or salt, e.g., an acid addition salt. Such salts include, without limitation, hydrochloride, sulfate, phosphate, citrate, fumarate, methanesulphonate, acetate, tartrate, maleate, lactate, mandelate, salicylate, succinate and other salts known in the art.
The Ar group is preferably but not necessarily a hydrophobic moiety. Typically, a hydrophobic moiety is comprised of non-polar chemical groups such as hydrocarbons or hydrocarbons substituted with halogens or ethers or heterocyclic groups containing nitrogen, oxygen, or sulfur ring atoms. Suitable hydrocarbons are C3-C13carbocyclic rings. Particularly preferred cyclic hydrocarbons include selected aromatic groups such as phenyl, 1-naphthyl, 2-naphthyl, indenyl, acenaphthyl, and fluorenyl and are represented by formulae (II), (III), (IV), (V), (VI), or (VII) respectively.
A suitable Ar group within the compounds of the present invention is a phenyl ring represented by formula (II): 
where R7, R8 and R9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, aryl and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C1-C6alkyl.
Other suitable Ar groups in compounds of the present invention are 1-naphthyl groups as represented by formula (II): 
where R10 and R11 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C1-C6alkyl.
Other suitable Ar groups in compounds of the present invention are 2-naphthyl group as represented by formula (IV): 
where R10 and R11 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C1-C6alkyl, as defined above.
Other suitable Ar groups in compounds of the present invention are aromatic groups represented by formula (V): 
where R12 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C1-C6alkyl.
Another suitable Ar group in compounds of the present invention is the acenaphthyl group as represented by formula (VI): 
Still another suitable Ar group in compounds of the present invention is the fluorenyl group as represented by formula (VII): 
In further preferred embodiments, the acenaphthyl group is a 1-acenaphthyl group, and the fluorenyl group is a 9-fluorenyl group.
In preferred embodiments of the invention, L is O, or NH, or N(C1-C6alkyl). N(C1-C6alkyl) refers to an alkyl-substituted N (nitrogen) atom, where the alkyl group has at least one and no more than six carbon atoms. These carbon atoms may be arranged in any linear, branched or cyclic fashion. Exemplary alkyl groups encompassed by C1-C6 alkyl include, without limitation, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, sec-butyl, t-butyl, cyclopropyl and cyclobutyl, cyclopentyl, methyl-substituted cyclopentyl (all isomers), and cyclohexyl, to name a few. A preferred alkyl group which may be bonded to the nitrogen atom is methyl.
In other preferred embodiments of the invention, for each of L being O (oxygen), NH or N(C1-C6alkyl), R1 is a direct bond, or a C1-C6 alkylene group, or a 1,2-disubstituted C5-cycloalkyl (i.e., 1,2-disubstituted cyclopentyl ring) or a 1,2-disubstituted C6-cycloalkyl (i.e., 1,2-disubstituted cyclohexyl ring). In another preferred embodiment, compounds of the invention have L and R1 both being direct bonds. In other preferred embodiments, R2 is methyl for each of the compounds having L being O, NH or N(C1-C6alkyl), and R1 being 1,2-disubstituted C6-cycloalkylene, or 1,2-disubstituted C5-cycloalkylene, or C1-C6alkylene.
The C1-C6alkylene group has at least one, and as many as six carbon atoms. These carbon atoms may be arranged in a linear or branched fashion, so long as the carbon atoms have two open valencies for bonding to L and one nitrogen of the piperazino moiety. Exemplary C1-C6alkylene groups include, without limitation, xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH(CH3)CH2xe2x80x94, and xe2x80x94CH2CH2CH2CH2CH(CH3)xe2x80x94, which illustrate both linear and branched arrangements, and the lower end (C1) and the upper end (C6) of the alkylene chain.
In a preferred embodiment, the compounds of the invention have the formula 
including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof. In this formula, the bond joining the Ar group (naphthyl group) to the sidechain (xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94Lxe2x80x94etc.) is shown between two carbon atoms of the Ar group (rather than being connected to any one particular ring atom), to thereby denote that the sidechain may be joined to the Ar group at any position thereof.
In other preferred embodiments, a compound of the invention has the following formula 
including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof. According to this embodiment of the invention, a preferred compound has L equal to N(CH3), and is referred to herein as compound XVa (which encompasses both trans enantiomers). Also according to this embodiment, another preferred compound has L equal to O, and is referred to herein as compound XVc, where compound XVc includes both trans enantiomers.
In other preferred embodiments, the compound of the invention has the formula 
including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof. According to this embodiment of the invention, a preferred compound has L equal to N(CH3), and when both enantiomers are present, is referred to herein as compound XVb.
In another preferred embodiment of compounds of the invention, when R1 is a direct bond, then L is also a direct bond. Thus, preferred compounds of the invention have the formula 
including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof. According to this embodiment of the invention, a preferred compounds has Ar equal to 1-naphthyl, and is referred to herein as compound XVIa, and has the following structure 
including salts, solvates, isolated tautomers, and mixtures thereof.
Also according to this embodiment of the invention, another preferred compounds has Ar equal to 2-naphthyl, and is referred to herein as compound XVIb, and has the following structure 
including salts, solvates, and mixtures thereof.
In another embodiment, the compound has one of the following formulas 
including salts, solvates, isolated tautomers, and mixtures thereof.
Certain compounds of the invention may be prepared by a method wherein a substituted acetic acid compound or activated version thereof, having the formula 
wherein X is OH or an activated (leaving) group such as chloride, is reacted with a compound of the formula 
The reaction provides a bond between Cxe2x95x90O and L as shown in the formula 
Compounds of formula Arxe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94X, wherein X is other than xe2x80x94OH, may be prepared from the corresponding acid (where X is xe2x80x94OH). These acid starting materials, such as 1-naphthalene acetic acid, 2-naphthalene acetic acid, phenylacetic acid, bromophenylacetic acid (including the 2-, 3- and 4-positional isomers), methylphenylacetic acid (also known as tolylacetic acid) and many other compounds of the formula Arxe2x80x94CH2xe2x80x94COOH are commercially available. See, e.g., Aldrich Chemical Co., Milwaukee, Wis.
A substituted acetic acid may be reacted with, e.g., thionyl chloride, to prepare an activated substituted acetic acid compound. Other synthetic protocols for preparing an activated acid may be found in, e.g., Szmuszkovicz, J.; Von Voigtlander, P. F. (1982) J. Med. Chem. 25: 1125-1126; U.S. Pat. No. 5,506,257 to MacLeod B. A. et al., U.S. Pat. No. 5,637,583 to MacLeod B. A. et al. and Clark, C. R. et al. (1988) J. Med. Chem. 31: 831-836.
The activated substituted acetic acid compound is then reacted with an amine or alcohol compound (depending on the identity of L) of the formula 
The preparation of 1,2-diaminocyclohexyl intermediates is described in, e.g., Szmuszkovicz, J.; Von Voigtlander, P. F. (1982) J. Med. Chem. 25: 1125-1126; and U.S. Pat. No. 5,506,257 to MacLeod B. A. et al. The preparation of 1-hydroxy-2-aminocyclohexyl intermediate is described in U.S. Pat. No. 5,637,583, also to MacLeod B. A. et al. The preparation of reactive carboxylic acid derivatives is described in the above references as well as in Clark, C. R. et al. (1988) J. Med. Chem. 31: 831-836.
The carboxylic acids may be coupled to the amine in the presence of a coupling reagent such as dicyclohexyl carbodiimide (DCC) or the like. The reaction is generally carried out in a suitable solvent such as tetrahydrofuran or dioxane at ambient temperature, but depending upon the reactivity of the specific starting materials employed, the reaction time, solvent employed and reaction temperature may be varied without undue experimentation by one of ordinary skill in the art, to achieve the desired coupling reaction. A reaction temperature of between about xe2x88x9225xc2x0 C. and the boiling point of the solvent are typically employed. The reaction between the activated carboxylic acid (e.g., acid chloride) and the amine is generally carried out at ambient temperature in a suitable solvent such as chloroform or dichloromethane in the presence of an acid acceptor (i.e., base) such as a tertiary amine or an alkaline metal carbonate or bicarbonate. The mixture of amine and acid halide is allowed to react until the reaction is essentially complete.
Compositions of the Present Invention
The present invention provides compositions, preferably pharmaceutical compositions, which contain at least one compound of the present invention as set forth above, and at least one pharmaceutically acceptable carrier or diluent, where the compounds of the present invention have formula (I) 
including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof, wherein, independently at each occurrence:
Ar is selected from a C3-C13carbocyclic ring, and ring systems selected from formulae (II), (III), (IV), (V), (VI), and (VII): 
where R7, R8 and R9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, aryl and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C1-C6alkyl; 
where R10 and R11 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C1-C6alkyl; 
where R12 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C1-C6alkyl; and 
including isolated enantiomeric, diastereomeric, tautomeric, and geometric isomers thereof, and mixtures thereof;
L is selected from the group of a direct bond, O, NH, and N(C1-C6 alkyl);
R1 is selected from the group of a direct bond, a C1-C6 alkylene group, and a 1,2-disubstituted C5-C6 cycloalkyl; and
R2 is C1-C6 alkyl.
The composition may include, for example, water. In a preferred embodiment, the composition is in the form of a tablet, and particularly a fast-release tablet for oral administration. A fast-release tablet (having a rapid disintegration time) is desired in order to provide the patient with a rapid onset of enhanced sexual performance and/or increased libido and/or relief of sexual dysfunction.
A xe2x80x9cfast-releasexe2x80x9d tablet will have a disintegration time of less than about one hour, preferably less than about 20 minutes, and more preferably less than about two or even one minutes. A suitable fast-release tablet contains 40 mg of a compound of the present invention, 8 mg of silicon dioxide (NF), 4 mg of stearic acid (NF), 212 mg of lactose (NF), 120 mg of microcrystalline cellulose (NF) and 16 mg of croscarmellose sodium (NF). A tablet containing these ingredients may be prepared by finely dividing and then mixing each ingredient together, then compressing the mixture into a tablet form. The tablet has a weight of about 400 mg. Other methods of mixing and tablet formulation will be readily apparent to one of ordinary skill in the art. A tablet prepared by this method will typically have a hardness of 10.7 Kp, an average thickness of about 0.2 inches and an average disintegration time of about 45 minutes.
Disintegrant compounds, such as croscarmellose sodium (NF) (available as Ac-Di-Sol from FMC Corporation), may be used to enhance the dissolution time of a formulation of the present invention. Other disintegrants such as potato starch, Explotab(trademark) sodium starch glycolate, Polyplasdone(trademark) XL crospovidone NF, Starch 1500(trademark) pregelatinized starch NF may be employed in the formulations of the present invention. Each of U.S. Pat. Nos. 5,731,339, 5,298,261 and 5,079,018 also describe formulations which demonstrate fast disintegration times, which may be employed to prepare a fast release formulation of the present invention.
Suitable disintegrants and methods for measuring disintegration time of tablets include Gissinger et al. xe2x80x9cA Comparative Evaluation of the Properties of some Table Disintegrantsxe2x80x9d Drug Development and Industrial Pharmacy 6(5):511-536 (1980); and European Pharmacopeia 1980.
The pharmaceutical compositions of the present invention may be in any form which allows for the composition to be administered to a patient. For example, the composition may be in the form of a solid, liquid or gas (aerosol). Typical routes of administration include, without limitation, oral, topical, parenteral (e.g., sublingually or buccally), sublingual, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal, intracavernous, intrameatal, intraurethral injection or infusion techniques. Pharmaceutical composition of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of one or more compounds of the invention in aerosol form may hold a plurality of dosage units.
For oral administration, an excipient and/or binder may be present. Examples are sucrose, kaolin, glycerin, starch dextrins, sodium alginate, carboxymethylcellulose and ethyl cellulose. Coloring and/or flavoring agents may be present. A coating shell may be employed.
The composition may be in the form of a liquid, e.g., an elixir, syrup, solution, emulsion or suspension. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, preferred composition contain, in addition to the inventive compounds, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer. In a composition intended to be administered by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.
The liquid pharmaceutical compositions of the invention, whether they be solutions, suspensions or other like form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer""s solution, isotonic sodium chloride, fixed oils such as synthetic mono or digylcerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. An injectable pharmaceutical composition is preferably sterile.
A liquid compositions intended for either parenteral or oral administration should contain an amount of the inventive compound such that a suitable dosage will be obtained. Typically, this amount is at least 0.01% of a compound of the invention in the composition. When intended for oral administration, this amount may be varied to be between 0.1 and about 70% of the weight of the composition. Preferred oral compositions contain between about 4% and about 50% of the inventive compound. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.01 to 1% by weight of active compound.
The pharmaceutical composition may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device. Topical formulations may contain a concentration of the inventive compound of from about 0.1 to about 10% w/v (weight per unit volume).
The composition may be intended for rectal administration, in the form, e.g., of a suppository which will melt in the rectum and release the drug. The composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient. Such bases include, without limitation, lanolin, cocoa butter and polyethylene glycol.
The compounds of the invention may be administered through use of insert(s), bead(s), timed-release formulation(s), patch(es) or fast-release formulation(s).
It will be evident to those of ordinary skill in the art that the optimal dosage of the substituted acetic acid derivatives of the invention may depend on the weight and physical condition of the patient; on the severity and longevity of the sexual dysfunction (when the goal is to treat sexual dysfunction); on the particular form of the active ingredient, the manner of administration and the composition employed. It is to be understood that use of a substituted acetic compound of the invention in a chemotherapy can involve such a compound being bound to an agent, for example, a monoclonal or polyclonal antibody, a protein or a liposome, which assist the delivery of said compound.
Therefore, the invention relates further to a pharmaceutical or veterinary composition comprising an effective amount of a substituted acetic acid derivative of formula (I) provided above, in association with a carrier.
In a further embodiment, the present invention is directed to the use of a substituted acetic acid derivative of the formula provided above (which includes physiologically acceptable salts and hydrates), for the manufacture of a medicament for treating, relieving or preventing the effects of sexual dysfunction. Thus, the substituted acetic acid derivatives of formula (I) provided above may be used for the manufacture of a medicament for treating, relieving or preventing the effects of male sexual dysfunction, preferably erectile inadequacy and inhibited male orgasm, especially erectile inadequacy. The substituted acetic acid derivatives of the formula provided above may also be used for the manufacture of a medicament for treating, relieving or preventing the effects of female sexual dysfunction, preferably sexual arousal disorder and inhibited femal orgasm, especially sexual arousal disorder.
In a further embodiment, the present invention provides a method for the treatment of a male or female patient suffering from sexual dysfunction, or a method to prevent sexual dysfunction in a patient (having, for example, a history of sexual dysfunction) comprising the administration thereto of a therapeutically or prophylactically effective amount of a compound of formula (I), or a composition including same, as provided above. The sexual dysfunction may be, for example, male erectile dysfunction or impotence. A patient that cannot obtain an erection may be treated according to the present invention, while a patient that cannot maintain an erection may receive a prophylactic dose of a compound of the invention in order to prevent premature loss of an erection.
In a still further embodiment, the present invention provides a method for increasing the libido of a male or female patient comprising the administration thereto of a therapeutically effective amount of a compound of formula (I), or a composition including same, as provided above.
In a still further embodiment, the present invention provides a method for enhancing the sexual performance of a male or female patient that is not necessarily exhibiting symptoms of sexual dysfunction, comprising administering to the patient in need thereof a therapeutically or prophylactically effective amount of a compound of formula (I), or a composition including same, as provided above. Enhanced sexual performance occurs when there is an increase in the type of behavior that is typically associated with the patient""s sexual activity or interest in sexual activity. Increased tone in the patient""s genitals is one indication of an enhancement of sexual performance. Enhancement of sexual performance may result in, e.g., a pro-erectile response in the patient, or an improvement in erectile function such as any increase in the ability of the patient maintain an erection, induce or improve ejaculation (e.g., have multiple ejaculations within a shortened period of time), or induce or improve orgasm. Specific examples of enhancements in sexual performance are described in connection with the pharmacological testing of compounds and compositions of the present invention, as set forth herein.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d refers to an amount which is effective, upon single or multiple dose administration to the patient, to enhance the libido and/or sexual performance of the patient receiving the compound or a composition containing the compound as provided above. Such an amount may serve to treat a sexual dysfunction, e.g., impotence in males, and/or to enhance the sexual desire and/or sexual performance of a patient without a sexual dysfunction. For example, the therapeutically effective amount may be administered to, for example, a bull, to promote increased semen ejaculation, where the ejaculated semen is collected and stored for use as it is needed to impregnate female cows in promotion of a breeding program. Increased sexual ejaculation is an example of enhanced sexual performance according to the present invention.
A therapeutically or prophylactically effective amount of a substituted acetic acid derivative of the invention is expected to vary from about 0.01 milligram per kilogram of body weight per day (mg/kg/day) to about 200 mg/kg/day. Preferred amounts are expected to vary from about 0.5 to about 80 mg/kg/day. A pharmaceutical composition containing a substituted acetic acid derivative of the invention may contain between 0.01 and 1% by weight of the active substituted acetic acid derivative, and between about 5 and 10% by weight glucose in order to increase the osmolarity of the solution. Two illustrative compositions are (1) 5 mg/mL of a substituted acetic acid derivative of the invention and distilled water in 100 mL total volume, and (2) 5 mg/mL of a substituted acetic acid derivative of the invention, 25 mg/mL glucose, and distilled water in 100 mL total volume.
In effecting treatment of a patient in need of an agent for treating sexual dysfunction and/or enhancing sexual performance and/or a pro-libido agent, a compound of the invention can be administered in any form or mode which makes the compound bioavailable in effective amounts, including oral, aerosol, and parenteral routes. For example, compounds of the invention can be administered orally, by aerosolization, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, topically, and the like. The compounds of the invention may be administered by direct injection into, e.g., the corpus cavernosa (intracavernously). The compounds of the invention may be administered intraurethrally (e.g., via an intraurethral catheter). The compounds of the invention may be administered topically, e.g., directly to the penis. The compounds may be administered intrameatally. Oral or aerosol administration is generally preferred. One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the condition to be treated, the stage of the condition, and other relevant circumstances. See, e.g., Remingtons""s Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990).
The compounds can be administered alone or in the form of a pharmaceutical composition in combination with pharmaceutically acceptable carriers or excipients, the proportion and nature of which are determined by the solubility and chemical properties of the compound selected, the chosen route of administration, and standard pharmaceutical practice.
In another embodiment, the present invention provides compositions comprising a substituted acetic acid derivative of the invention in admixture or otherwise in association with one or more inert carriers. These compositions are useful, for example, as assay standards, as convenient means of making bulk shipments, or as pharmaceutical compositions. An assayable amount of a compound of the invention is an amount which is readily measurable by standard assay procedures and techniques as are well known and appreciated by those skilled in the art. Assayable amounts of a compound of the invention will generally vary from about 0.001% to about 75% of the composition by weight. Inert carriers can be any material which does not degrade or otherwise covalently react with a compound of the invention. Examples of suitable inert carriers are water; aqueous buffers, such as those which are generally useful in High Performance Liquid Chromatography (HPLC) analysis; organic solvents, such as acetonitrile, ethyl acetate, hexane and the like; and pharmaceutically acceptable carriers or excipients.
More particularly, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a substituted acetic acid derivative as disclosed above, in admixture or otherwise in association with one or more pharmaceutically acceptable carriers or excipients.
The pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art. The carrier or excipient may be a solid, semi-solid, or liquid material which can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art. The pharmaceutical composition may be adapted for oral, parenteral, or topical use and may be administered to the patient in the form of tablets, capsules, solution, suspensions, or the like.
The compounds of the present invention may be administered orally, for example, with an inert diluent or with an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should preferably contain at least 4% of the compound of the invention as an active ingredient, but this amount may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit. The amount of the compound present in compositions is such that a suitable dosage will be obtained. The tablets, pills, capsules and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
For the purpose of parenteral therapeutic administration, the compounds of the present invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1% of a compound of the invention, but this amount may be varied to be between 0.1 and about 50% of the weight thereof. The amount of the inventive compound present in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.01 to 1% by weight of active compound.
The compounds of the present invention may also be administered by aerosol. The term aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system which dispenses the active ingredients. Aerosols of compounds of the invention may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient. Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, spacers and the like, which together may form a kit. Preferred aerosols are able to be determined by one skilled in the art.
The compounds of this invention may also be administered topically, and when done so the carrier may suitably comprise a solution, ointment or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Topical formulations may contain a concentration of the inventive compound of from about 0.1 to about 10% w/v (weight per unit volume).
The solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred carrier or diluent.
The substituted acetic acid derivatives of the invention may be combined with one or more known pharmacological agents used in the treatment and/or prevention of sexual dysfunction and/or known to enhance the libido and/or sexual performance of a patient receiving the pharmacological agents.